JP2003521217A - Methods and compositions using fermented red rice products - Google Patents

Abstract

Methods and compositions are disclosed which comprise red rice fermentation products, that can be used as natural dietary supplements and/or medicaments for the treatment or prevention of hyperlipidemia and associated disorders and symptoms, such as cardiovascular diseases, cerebrovascular diseases, diabetes, hypertension, obesity, asthenic breathing, chronic headache, chest pain and tightness, limb swelling and distention, loss of appetite and excess expectoration. The methods and compositions are effective in lowering both the serum cholesterol and serum triglyceride levels in humans, and can be used for maintaining cardiovascular health. The invention also encompasses particular Monascus strains that yield fermentation products with the desired biological activities.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to the field of rice fermentation and treatment of hyperlipidemia. In particular,
The present invention relates to fermented products and methods of red rice and to the use of said products for the treatment of high cholesterol levels and other diseases.

[0002]

[Prior art]

The present invention relates to a composition comprising a fermentation product of red rice, the composition comprising dietary supplements and / or therapeutic therapeutic agents.
ents). For example, the composition can be used to lower cholesterol and triglycerides in the blood of mammals. further,
The present invention relates to a method of treating cardiovascular and other diseases using red rice fermentation products. In addition, the present invention relates to a particular Monascus strain that produces a fermentation product with the desired biological activity.

[Ancient Chinese Red Rice] Red rice is known primarily for its use in food as a preservative and colorant and for its use in the dyeing industry. Red rice (known in China as Hongqiu or Hong Qiuyu) is known and has been used in China for hundreds of years in the production of rice liquor and as a food preservative. In addition, red rice is known as a source of ancient Chinese medicine or certain ancient Chinese prescription drugs.

Red rice was first used throughout the Han dynasty. Tao Gu, who lived in the fifth generation after the Tang dynasty, said in Qin g Yi Lu
"Red Yeast Rice Cooked With Meat" was recorded. The method for producing red rice was first recorded in the T'ien Kyng K'ai Wu and the herbs. A detailed description of the use of red rice as a medicine can be found in the Ming Dynasty (1368).
~ 1644), it is defined in the Order of the Herbaceous, an ancient Chinese prescription book.
Red rice is described in the herbaceous family as mild and non-toxic and useful in the treatment of dyspepsia and diarrhea. Red rice has also been described as useful for improving blood circulation, promoting spleen and stomach health. In addition, some "prescription drugs" that use red rice for the treatment of digestive tract and heart and abdominal pain such as indigestion and diarrhea.
Is also regulated in this ancient work. According to the Traditional Chinese Medicine Standard explained in the Chinese Pharmacopoeia and Beijing, Inner Mongolia, Shandong, Jiangsu, and Hunan other traditional Chinese medical standards, red rice is traditional. It is used in detail as a traditional Chinese medicine. Furthermore, in the textbooks of Chinese universities such as food additives and food chemistry, red rice is considered as an additive in foods and beverages, for the production of items such as fermented tofu, beer and meat. Widely used in the food processing industry.

[0005] In an English-language abstract of the Herbaceae, published in 1911, red rice is described as useful for fermentation and of medicinal value in the treatment of postpartum disorders in women and dyspepsia in children. 223- in Stuart, M.D., "Chinese Materia Medica-Vegetable kingdom"
234, republished in 1979 by Southern Material Center, Inc., Taipei, Republic of China). The red rice pictured in the genus Lepidoptera was recognized as a yeast species known as Monascus purpureus Went (Reed, BEE, 1936, “Chinese from the genus Lepidoptera”). Chinese Medicinal Plants from the Ts'ao Kan Mu ", published by Pekin National History Bratain; Klein, Gae, 1932, Handbuch Pflanzenanalyse II, p.
1422-1423, Vienna, Verlag von Julius Springer.

The formation of red rice has been reported in other publications since the Ming Dynasty, namely A. D. Sung Ying-Hsing, published in 1637, "T'ien Kung K '.
ai Wu ”(T'ien Kung K'ai Wu-Chinese technology in the seventeenth, an English translation of this ancient work.
century), translated by E-tu zen Sun, Shiou-Chuan Sun, Pennsylvania State University Press 1966, 291
~ 294). Red rice is described therein as being useful for preserving the color or taste of fish or meat. The formation process used red wine mash to cook non-sticky rice as a starting material. In addition, a method for producing red rice by allowing yeast to grow on the surface of cooked rice was recorded by Vorerman (1984, Anarecta of Chromatologieche Gebide II, Genneche, Filschrift). Fall Ned Indie (Analec
ta ob Cromatologisch Gebied.II. geneesh Fylschrift voor Ned. Indie）, 3
5, No. 5).

Even nowadays, red rice, a fermentation product of a strain of Monascus, is still used in Asian and North American Asian societies for traditional Chinese medicine, wine making and food coloring. The red and yellow pigments of Monascus perpleus, such as monascorubin and monascin, have been purified and studied in detail (Fielding et al., 1961, J Chem Soc, 4579-4589). The culture conditions and their effect on the coloring of Monascus perpleus were also studied (Broder et al., 1980, J Food Soc, 45, 567-469). Antibacterial activity, especially against Bacillus spp., Was also found in Monascus perpleus extracts (Wong, 1977, Plant Physiol, 60, 578-5).
81). Traditional methods of red rice have been shown to be of no value and have gradually fallen out of use in pharmaceutical applications. Traditional red rice has no blood fat reducing effect and is never used as a cholesterol lowering agent.

Hyperlipidemia and Dietary / Pharmaceutical Intervention Fat and lipoproteins play a special role in the transport of fat-extracted metabolites between organs for absorption, metabolism and partitioning ( Ferrig et al., 1975, NENG
J MED, 293, 1078-1084). It is very common for diet-induced susceptibility to elevated levels of fat in the blood, including cholesterol.
The interaction of genetic predisposition linked to inactivity with a high-fat, high-calorie diet causes heart disease, hypertension, hyperglyceremia and diabetes in a significant proportion of the United States population.

High cholesterol in the blood is a major risk factor for coronary artery disease. Cholesterol is the major component of the spots of atherosclerosis. Others associated with reduced HDL cholesterol levels, especially those associated with adiposity, including hyperglyceridemia, have been identified as sources of cardiovascular disease risk. There is a complementary association between elevated triglyceride levels and reduced HLD levels.

The level of cholesterol in the blood circulation is a result of the balance between the production of apoB-100 (apoB-100) particles and their migration out of the blood circulation. Cholesterol is synthesized from acetyl-CoA via a series of 20 or more enzymatic reactions. This biosynthetic cycle is mainly composed of HMG-CoA reductase (hydroxymethylglutaryl coenzyme A reductase) that catalyzes the reduction of HMG-CoA to mevalonate.
Is adjusted by the activity of. Since most of the circulating cholesterol is synthesized in the liver due to in vivo conditions and is not extracted from dietary cholesterol, inhibitors of enzymes involved in cholesterol biosynthesis have been sought as therapeutic agents for hypercholesterolemia. (Grandy, New Eng J Med (1988), 319, 24 ~
33).

A group of compounds is H, a key enzyme in the cholesterol biosynthetic pathway.
It inhibits cholesterol biosynthesis by competing with the natural substance for MG-CoA reductase (HMG-CoA). The first such hypocholesterolemic compound discovered was compactin, which was separated from the culture fluid of Penicillium citrium by Akira Endo (Endo et al., J Antibiotics, (1975). 29, 1346-1348, and U.S. Pat. Nos. 3,983,140, 4,049,495 and 4,137,322). The hypocholesterolemic activity of this compound has been demonstrated in several animal species (Tujita et al., Atherosclerosis (1979) 32, 307-313). Subsequently, a hypocholesterolemic compound structurally related to compactin was independently found by endo from the fermentation product of monascus ruber (the active compound was named monacolin K. Endo, J Antibiotics. , (197
9) 32, 852-854; Endo, J Antibiotics, (1980) 33, 3
34-336; see also German patents DE 3051175, 3051099 and 3006216, British patents GB 20467737 and 2055100).
, And by other groups Aspergillus terreus
Was found in the culture fluid of. The active substance is also named mevinolin, lovastatin or Mevacor® (Tbert et al., J Clin Invest (1982) 69, 913-919) and as a drug delivered according to prescription, Available in the United States since 1987. The medicinal and long-term adverse effects of this active substance were reconsidered (Tbert, Am J Cardi
ol, 62, 28J-34J). A method for producing the isolated active substance, its derivative and asparagillus has been reported. U.S. Pat. No. 4,231,938, 43427
67, 4294926, 4319039, 4294926, 42948
See 46 and 4420491.

[0012]

[Problems to be Solved by the Invention]

Although monacolin K or mevinolin have been used successfully in the treatment of hypercholesterolemia, the compounds have no or insignificant effect on blood triglyceride levels. Other fat-regulating agents used in the treatment of hyperglyceridemia, particularly type IV and V hyperlipidemia, are nicotinic acid (eg niacin) and fibric acid derivatives (eg gemfibrozil and clofibrate ( clofibrate)). However, its side effects, such as gastric hypersensitivity, hyperuricemia, when taking large amounts of niacin,
The use of such agents is limited because hyperglyceremia, pruritus can occur and gemfibrozil can lead to malignancy, gallbladder disease and abdominal pain. Moreover, the risk of myositis and rhabdomyolysis resulting from renal failure is increased when monacolin K is combined with gemfibrozil, clofibrate or niacin. Such combinations are only used with careful control under special conditions justified by danger (Merck Manual, 1992, 16th edition, pp. 1044-1046). High levels of triglycerides in blood are known to be a risk factor in various disease states and are a medical complication. Thus, there is a need for the development of compositions that achieve reduced blood levels of both triglycerides as well as cholesterol. Regular exercise, proper nutrition and weight loss programs can prevent or reduce the development of normal lifestyle-related diseases such as heart disease associated with elevated blood fat (Pee Sanya, Am J. Clin Nutr (1991) 53, 1595S to 1603S). The role of diet in maintaining optimal health and delaying and reversing disease progression are challenges of much research and public attention. The development of effective dietary supplements for use in the treatment of mixed hyperlipidemia, which can be used both with and without dietary changes, is of great benefit.

[0013]

[Means for Solving the Problems]

The present invention relates to a fermentation product of at least one strain of Monascus, for use as a dietary supplement to lower the levels of both cholesterol and triglycerides in the human body or as a therapeutically active medicament. be able to. The invention is in part due to the fact that certain red rice products, i.e. the fermentation products of certain strains or mixtures of strains of Monascus, are not only found in mammals, especially humans, but also in blood as well as in blood cholesterol levels. This is based on the surprising finding that lowering the triglyceride level of s. Monacolin K and mevinolin are not known to be significantly effective in lowering blood triglyceride levels, so the beneficial effects of red rice products may be due to other components of the fermentate. is there.

In various embodiments of the present invention, red rice is not limited to normal dietary supplements or cardiovascular disease, but is not limited to diabetes, fatty liver conditions, stroke, cerebral thrombosis, hypotension, hypertension and obesity. It can be used as a medicine for treating or preventing various diseases including, and for controlling the level of circulating fat such as cholesterol and triglyceride. Further, the invention includes a method of treating or preventing these diseases in humans, which method comprises administering to the human a therapeutically effective amount of a red rice fermentation product. The present invention also includes a method for improving or maintaining cardiovascular health in humans, the method comprising administering an effective amount of a red rice fermentation product. Further, the present invention includes a method of reducing blood cholesterol and blood triglyceride levels in humans to normal levels, the method comprising providing a therapeutically effective amount of a red rice fermentation product to humans. Consists of administering. Red rice is also
It can be used to treat or prevent various chronic diseases or conditions associated with cardiovascular disease.

In accordance with the present invention, red rice can be manufactured into various dosage forms. Also disclosed is a method of making red rice based on traditional fermentation methods.

The term “red rice yeast” or “monascus” as used herein refers to a fermentation precursor, while “red rice”, “red rice product”, “red rice extract” ", Etc., refers to the product resulting from at least one fermentate of Monascus. In addition, the latter term includes traditional red rice products and improved red rice products described below. More specifically, the "red rice product" used here is
Represents a fermentation product, for example one or a mixture of red rice yeast fermentation products. Strains of Monascus (such as strain 0272) that "produce Robustatin" are at least 0.
． It is one that can be fermented to produce a product with a content of Robustatin of 05%, preferably at least 2%.

The red rice product is at least one fermentation product of the following Monascus yeast shown in the table below.

Red rice is one or mainly Monascus perpleus wento and a smaller proportion of other strains of Monascus, such as Monascus ruber van Tieghem, Monascus furisinosus satoto ( Monascus fuliginosus Sato), Monascus Pirosus Sato
s Pilosus Sato) and Monascus albidus Sat
o) is a fermentation product of a mixture of Monascus yeast consisting of Red rice is also a strain of the following Monascus yeast, Monascus perpleus Went ATCC301.
41, AS3.562, AS3.991, AS3.4446 [ATCC1636
5], AS3.4642 [NRRL2897], AS3.4464 [NRRL9
6], AS3.4644, AS3.4645, AS3.4651; Monascus
Louver van Tiegem AS3.549, IFFI05007, IFFI
05008, IFFI05010, IPPI05011; and Monascus anka IFFI05038 (Chaina Catalogu
e of Cultures, 1992, China Committee on Microbial Cultures Collection (C
haina Committee for culture Collection of Microorganism), China Machine Press (Chaina Machine Press), Pekin, 1992). The improved red rice of the present invention are Monascus perpleus Went mutant strains M4027, M4028 and M4184.

[0019]

[Table 1]

As used herein, the term “traditional red rice” refers to a red rice product that is the result of fermentation using a mixture of Monascus yeast that is traditionally used to make red rice. . "Traditional red rice" generally contains no more than about 0.005% by weight robastatin. In accordance with the present invention, "improved red rice" is produced by fermentation with one or more natural or mutant strains of Monascus and has improved biological or nutritional properties, such as traditional Produces fermented products with higher and lower cholesterol levels than fresh red rice. The improved red rice of the present invention is the Monascus perpleus Went mutant strain CGMCC No. 0
It consists of 272. Several other strains can be used to achieve the goals of the invention. Improved red rice is here, sometimes in Xuzhikang
Quoted as.

In general, the red rice product of the present invention is a purplish red powder with a slightly bitter but mild and pleasant taste. Similarly, the red rice product has a pleasant odor. Color and / or odor may vary depending on the fermentation process, the strain used and each step of the fermentation process. The red rice product of the present invention comprises at least 0.05% by weight of Robustatin,
More preferably it comprises at least about 2.0% Robustatin.

As used herein, the term “effective treatment” refers to the alleviation of a particular symptom or a significant change towards the normal value of a particular laboratory test. Preferably, the symptoms are reduced by at least 30-70% and the laboratory values shift by at least 10% towards normal values. More preferably, the symptoms are reduced by 70% and / or the laboratory values shift by at least 20% towards normal values. Most preferably, treatment is effective if symptoms are alleviated by 90% and / or laboratory parameters return to normal values.

The term “hypercholesterolemia” means a condition in which the level of cholesterol in the blood is elevated.

As used herein, the term “therapeutically effective amount” or “therapeutically effective dosage” is in the treatment or prevention of disease or in regulating the levels of fat and lipoproteins in the blood. , Means the amount of a special drug that provides a therapeutic benefit.

As used herein, the term “dietary supplement” means an additional element added to the daily food intake of mammals, usually humans.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below.
All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages will be apparent from the following detailed description and claims.

[0028]

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a composition consisting of a fermentation product of at least one strain of Monascus. These compositions are useful in mammals, and especially in humans, for reducing levels of both cholesterol in blood and triglyceride in blood. Further, the composition provides blood levels to maintain healthy levels despite internal (eg, aging) or external (eg, stress) factors that affect blood cholesterol and triglyceride levels. Is useful for controlling both cholesterol and triglyceride levels. The compositions and methods of the present invention are based, in part, on the discovery that fermentates of strains of Monascus have hypocholesterolemic properties and exhibit the unexpected ability to lower levels of triglycerides in blood. Since monacolin K is known to be not significantly effective in lowering the level of triglycerides in the blood, the beneficial effects of red rice products should be related to other components of the fermentate. The ability of red rice products to lower the levels of triglycerides in the blood provides a technology that involves the use of prescription-required hypocholesterolemic blood compounds and, in the alternative, creativity and naturalness.

According to the present invention, traditional or improved red rice can be produced by traditional fermentation procedures or by modifications of traditional procedures. According to the earliest reported method (Swen, 1637, Tianjuu, pages 291-294, English translation by Swen et al., Pennsylvania State Press, 1966), red rice
Manufactured by fermentation of non-sticky rice that has been washed and cooked with red wine mash, natural juice of Polygonum herbs and alum water. Rice is fermented in air on bamboo plates for 7 days under very clean conditions. Rice is harvested as red rice, changing its color from white to black, from black to brown, from brown to red, and from red to yellow. According to an alternative traditional method, the non-sticky rice can be fermented in holes in the soil covered by a tightly covered bamboo mat. Fermentation may take place underground for 1 year or more and 4 years or less.

In the context of the present invention, the traditional method is improved by using modern fermentation techniques and equipment to more precisely control the temperature, pH, pressure and other fermentation parameters, which reduce the fermentation time, among others. Has been done. A key feature of improved red rice production is the inclusion of active ingredients that can prevent or treat hyperlipidemia and related cardiovascular disease. The formulation can be as follows.

Traditional Culture Formulation For all vehicle formulations, rice or other grains are used as a carbon source. The carbon source may be rice (polished rice long grain non-sticky rice, milled round grain non-sticky rice, milled sticky rice, red rice and black rice), millet, barley, wheat or It can be a corn. Furthermore, sugar and substances containing sugar can be used. Organic compounds such as glycerin or glycerides can also be used for the vehicle formulation. 30-80m for every 100g of polished non-sticky rice
l of culture medium is added. The key characteristics of the culture medium are that the carbon source is selected from the group consisting of cereals, sugars and organic compounds, and the nitrogen source is beans (eg soybean flour, compressed soybean cake) or peanut flour (or compressed peanut cake). ),
Peptone, rice extract powder, concentrated beef juice, silkworm pupa powder or inorganic salt (
For example, it may be selected from the group consisting of NH ₄ NO ₃ etc.) and a phosphorus source such as an inorganic salt (eg KH ₂ PO ₄ , K ₂ HPO ₄ etc.) may be added. Also,
Other inorganic salts such as MgSO ₄ , FeCl ₂ may be added. By way of non-limiting example, the methods of one example are listed below as vehicle formulations of the present invention.

Medium 1, liquid system 2-7% glycerin (or malt or potato juice) 2-6% sugar 0-3% peptone 0.5-3% yeast extract powder 0-3% Concentrated beef juice (selective) 2-4% defoamer (eg soybean oil or peanut oil) water [medium 2, solid system] 0-5% potato juice 0-6% sugar 0-1.5% Yeast extract or peptone 30-80 ml water per 100 g rice [Medium 3] 2-4% potato juice 2-6% sugar 0.5-3% yeast extract powder (or peptone or concentrated beef juice) A mixture of about 40-80 ml of water is added for every 100 g of rice, the pH is maintained at 3-8 and pasteurized with steam at 121 ° C.

Generally, the pH is adjusted to 3.0-5.0 and the mixture is steam sterilized (121
C). The mixture is cooled to 40 ° C. and rice is inoculated with the Monascus strain of the invention. For example, Monascus perpleus Went strain CGMCC No. 0272
Is added and the mixture is incubated at 15 to 35 ° C for 9 days. Fermentation of the mixture is preferably 1
It is carried out at a temperature of 5 to 35 ° C., most preferably 20 to 28 ° C., for 4 days or longer, most preferably 9 days or longer until the formation of red rice is noticed. Any one of a number of fermentation methods may be used, as is well known to those skilled in the art. For example, Erlenmeyer flasks, trays or ventilated fermentation beds may be used as fermentation equipment.
At the end of the fermentation process, the fermentation broth is drained and disposed of, while the solid residue is sterilized by heat (eg by high pressure steam). For example, the fermentation product is 69-12
Sterilized at a temperature of 1 ° C. and dried. The dried product is ground. capsule,
Standard mesh sizes for tablets, powders and suspension products are well known in the art. According to the method of the example, the improved red rice of the present invention is about 60-8.
Grind to 80 mesh under vacuum at a temperature of 0 ° C. and collect the powdered product. This product can be used directly in the various compositions and forms provided by the present invention. For example, the product can be filled into capsules. Alternatively, the 80 mesh ground product can be further ground to 200 mesh. The 200 mesh powder can be formed into tablets by standard methodologies. Alternatively, red rice in liquid or syrup form can be made using traditional methods.

Alternatively, the dried and ground red rice powder can be further processed. The processing is, for example, extraction with an organic solvent such as, but not limited to, alcohol (eg 75-90% ethanol) to remove starch and / or agar. After evaporation to dryness, extraction can be used in various compositions and forms provided by the present invention. The extracted product can be concentrated to dryness under vacuum and evaporation (60-80 ° C, 0.06-0.08 MPa). This provides an exceptionally useful supplement at a very low cost.

In accordance with the present invention, “improved red rice” means a fermentation with improved biological or nutritional properties, such as higher hypocholesterolemic and hypotriglyceridemia activities than traditional red rice. Produced by fermentation with a strain of one or more natural or mutant strains of Monascus that produces a product. The improved red rice of the present invention consists of the Monascus perpleus Went mutant strains M4027, 4028 and M4184. Some other strains (Chainese Mic
roorganism Strain Index), 1992, China Microorganism Collection Commission (Chain
a Microorganism Collection Committee)) can be used to achieve the objects of the invention, as listed in the table above.

Robustatin in red rice is extracted with 10 ml of 75% EtOH at ambient temperature. Extract (2 ml) is treated for 30 minutes with 75% EtOH solution 1ml of 0.06 mol NaOH, 0.06 moles of H ₃ PO ₄ 1ml (75% EtO
H solution). The mixture was a C18 HPLC column (150 x 4.60
mm) and 0.02 N to quantify the amount of Robustatin present.
Of H ₃ PO ₄ (70% MeOH solution).

Red rice is a normal dietary supplement or for treating various diseases including diabetes, stroke, hypertension and obesity for preventing diseases (maintaining health) or not limited to cardiovascular diseases. And as a pharmaceutical to regulate circulating levels of fats and lipoproteins such as cholesterol and triglycerides. Red rice can also be used to treat or prevent various conditions associated with cardiovascular health associated with the above-mentioned diseases and impaired by aging and other internal and external factors.

As used herein, examples of cardiovascular disease may include, but are not limited to myocardial infarction, coronary heart disease, atherosclerosis, arteriosclerosis.
The present invention includes the treatment and prevention of stroke, cerebrovascular disease such as stroke memory loss and cerebral thrombosis.

The present invention is also useful for humans to treat or prevent hyperlipidemia, cardiovascular disease, cerebrovascular disease, hypertension, hypotension, diabetes, fatty liver condition or obesity or their complications. , A composition comprising a therapeutically effective amount of red rice, for example 2 to 4 g per day.

The present invention further provides for controlling the levels of fat and lipoproteins in the blood in humans in the need of treatment in order to maintain the levels of fat and lipoproteins within a healthy normal range. A composition comprising a useful, therapeutically effective amount of red rice is included. In one aspect of the invention, the composition is suitable for use in treating or preventing hyperglyceridemia. In a more preferred embodiment,
Such compositions are used to reduce cholesterol and triglyceride levels in human blood.

The present invention further includes compositions comprising a therapeutically effective amount of an improved red rice product useful for the treatment of any one of the following conditions: Lack of breathing, weak breathing, drowsiness, dizziness, habitual headache, chest pain and pressure, heartache, loss of appetite, swelling of limbs, pressure and swelling.

Improved Red Rice Function The improved red rice and improved red rice formulations of the present invention include a statinoid compound, namely the hydroxyacids Robustatin and Lactone Robustatin.

[0043]

[Chemical 1]

[0044]

[Chemical 2]

Without being limited by theory, the Monascus strains described above have an increased content of statinoid compounds when cultured under suitable fermentation conditions. Increased statinoid compounds reduce cholesterol in blood and triglycerides in blood, while at the same time increasing high concentrations of lipoprotein cholesterol.

The red rice of the present invention can be used for the treatment of hyperlipidemia, while at the same time it can be used for atherosclerosis, coronary heart disease, myocardial infarction, hypertension and cerebral thrombosis, and others around it. Is associated with such cardio-cerebrovascular diseases.

Methods of Treatment The present invention provides methods for the treatment of humans who are afflicted with various diseases, disorders and conditions. In addition to treating human diseases, the methods of the invention can also be used for prophylactic treatment in those who are susceptible to such diseases, disorders and conditions.

The present invention comprises administering to a human a therapeutically effective amount of a red rice product or a composition comprising said product, which may include hyperlipidemic disease, cardiovascular disease, cerebrovascular disease, hypertension. Illnesses (hereditary and non-hereditary), hypotension, angina, stroke, diabetes, fatty liver conditions or obesity or their complications in humans.

The present invention also comprises administering a therapeutically effective amount of the red rice product of the present invention, comprising: hyperlipidemic disease, cardiovascular disease, cerebrovascular disease, hypertension, hypotension, Includes methods of preventing angina, stroke, diabetes, fatty liver conditions such as fatty liver deposits, obesity or their complications. The methods of the invention are preferably used to treat or prevent hyperglyceridemia and relate to diseases such as diabetes in humans.

As used herein, examples of cardiovascular disease include stroke, cerebral thrombosis or memory loss due to stroke, myocardial infarction, coronary heart disease, atherosclerosis, arteriosclerosis and cerebrovascular disease. Or including status.

The present invention also comprises administering to a human a therapeutically effective amount of a red rice product or a composition comprising said product, the levels of fat and lipoproteins being in the healthy normal range. In the need of lowering the amount of fat and lipoproteins in the blood in humans. In a preferred embodiment, the method of the invention is used to reduce blood cholesterol and triglyceride levels in humans. The method of the present invention is particularly useful for the treatment of geriatric patients and postpartum women.

The present invention further comprises administering to a human a therapeutically effective amount of a red rice product or a composition comprising said product, which comprises lack of breathing, weak breathing, lethargy, dizziness, Provided are methods for treating humans susceptible to addictive headaches, loss of appetite, limb swelling, pressure and distension and abdominal distension or complications thereof.

The therapeutic or prophylactic dosage of traditional or improved red rice in the control of fat and lipoproteins in the blood, as well as in the treatment or prevention of disease, depends on the condition to be treated and the treatment. It depends on the severity of the condition. The dosage and perhaps dose frequency, will also vary according to the age, weight and response of the individual patient. In general, for the conditions described herein, the range of total daily dosage of red rice is
About 0.1 g to about 5 g administered in a single or divided oral dose. For example, a preferred oral daily dose range is from about 0.3 g to about 4 g, and a most preferred oral daily dose is from about 1.2 g to about 2.5 g. For example, two capsules, each containing 0.6 g of red rice, should be combined with one capsule to obtain the desired dosage.
It is taken orally twice daily. One course of treatment is at least 4 weeks. It will be apparent to those skilled in the art that it may be necessary to use dosages outside this range in some cases. Furthermore, it is noted how a nutritionist, nutritionist, clinician or treating physician knows when to interrupt, coordinate or end-of-life treatment in coordination with an individual patient's response.

It should be noted that the present invention encompasses traditional new uses of red rice, new red rice products, and new processes using these products.

Use of Dietary Supplements As noted above, the present invention includes compositions and methods that use traditional and new or improved red rice products as dietary supplements. As such, red rice products are found to reduce cholesterol and triglyceride levels in the blood despite essential deterioration resulting from, for example, aging and external factors such as stress, lack of exercise and poor nutritional support. Individually provide techniques to maintain normal or healthy levels. Dietary supplements also provide a method for preventing, or reducing the likelihood or experience of, the diseases discussed above. Finally, dietary supplements can be used to prevent weight gain or obesity. Finally, dietary supplements containing red rice products are particularly useful for the elderly and postpartum women. Dietary supplements should be taken daily for 4 weeks and can be used permanently on a daily basis. The daily dosage is from about 0.1 g to about 5.0 g, preferably from about 1 to about 4 g, most preferably about 1.2 per day.
To about 2.4 grams.

[Formulation] The pharmaceutical preparation and dietary supplement of the present invention comprise a red rice product or an extract thereof as an active ingredient, and also include a pharmaceutically acceptable carrier or excipient and optionally Other components may be included. Other ingredients that can be incorporated into the diet or pharmaceutical composition of the present invention may include, but are not limited to, vitamins, amino acids, metal salts and flavor enhancers. For oral administration, the composition of red rice can be added directly to the food, so that a therapeutically effective amount of red rice is ingested during a normal diet. Any method known to those of skill in the art may be used to add or incorporate red rice into natural or processed foods.

Compositions of the invention suitable for oral administration may be formulated as discrete units, such as capsules, cassettes or tablets, each containing a predetermined amount of red rice product, as a powder or granules, or water-soluble. It may be provided as a solution or suspension, such as a liquid, a water insoluble liquid, an oil-in-water emulsion, a water-in-oil liquid emulsion. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping it into the desired presentation. The composition of the present invention additionally comprises a binder (eg pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose), a binder or a filler (eg
Lactones, pentosan, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (eg magnesium stearate, talc or silica), disintegrants (
For example, potato starch or sodium glycolate starch) or a moisturizer (eg sodium lauryl sulphate) may be included. The tablets or capsules can be coated by methods known in the art.

Liquid formulations for oral administration may be taken, for example, in the form of liquids, syrups or suspensions, or to make up the formulation with water or other suitable vehicle before use. Can be provided as a dry product. Such liquid formulations include suspensions (eg sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifiers (eg lecithin or acacia), non-aqueous vehicles (eg almond oil, oily esters, It can be prepared by a conventional method together with pharmaceutically acceptable additives such as ethyl alcohol or fractionated vegetable oil) and preservatives (for example, methyl- or propyl-p-hydroxybenzene or sorbic acid). The formulations can also be made like similar food products with buffer salts, flavoring agents, colorants and sweeteners as preferred.

Any dosage form may be utilized to provide the patient with effective dosing of the red rice product. Dosage forms include tablets, capsules, dispersions, suspensions, solutions, capsules and the like. Because of their ease of administration, tablets and capsules provide the most advantageous oral dosage unit form. In that case, the solid pharmacological carriers mentioned above are utilized. In addition to the usual dosage forms set forth above, the pharmaceutical formulations of the present invention may also be administered by a controlled release means. However, the most preferred oral solid pharmaceutical formulation is a capsule.

[0060] For example, tablets are manufactured by pressing or shaping, optionally with another auxiliary ingredient. Pressed tablets are made by pressing red rice in a free-flowing form such as powder or granules by a suitable machine, optionally with a binder, lubricant, inert diluent, surfactant or dispersant. Mixed with. Most preferably, the composition is a capsule containing 0.3 g of red rice in powder form.

The present invention is further clarified with reference to the following examples, which describe detailed human clinical trials conducted to study the efficacy and safety of red rice. It will be apparent to those skilled in the art that numerous modifications of both materials and methods may be implemented within the scope of the invention.

The invention will be further described in the following examples. The examples are intended to further provide an illustration of the invention and are not intended to limit the scope of the claims.

[Example 1-Preparation of red rice culture broth] (A) The liquid culture broth contains 2-4% glucose, 3-5% glycerin, 0-
3% thick beef juice, 0.8 to 1.6% of peptone, 0-3% yeast extract powder, 0.1% KH ₂ PO _4, and 0.05% of MgSO ₄ · 7H ₂ O And water. Two media were prepared. The first is 2% glucose, 3% glycerin, 1.5% concentrated beef juice, 0.8% peptone, 3%.
% Yeast Extract Powder, 0.1% KH ₂ PO ₄ , and 0.05% MgSO ₄
Contains 7H ₂ O and water, the second contains 4% malt juice or potato juice, 8% sugar, 1.5% yeast extract powder, 3% concentrated beef juice and water. The pH was adjusted to 3.5 with acetic acid. 50 for each culture
100 ml of polished, round-grain, non-sticky rice was added to ml, and the medium was 121
Sterilized by steam at ℃. The mixture was cooled to 40 ° C. or lower, inoculated with Monascus perpleus Went (CGMCC No. 0272) in a glass tube or plate, and cultured at 30 to 34 ° C. for 24 to 36 hours. The fermentation was continued for 9 days at 25 ° C. As soon as the fermentation period was completed, the mixture was sterilized at high temperature (100-121 ° C), dried under vacuum at 80 ° C and ground to 60-100 mesh. The powder was filled into capsules. Yield, about 65%.

(B) Alternatively, 4% malt juice or potato juice, 8%
A culture solution containing 3% glucose, 3% concentrated beef juice, 3% peptone and water (pH value adjusted to 3) was used. The resulting product of the subsequent fermentation was extracted with 75-95% ethanol. Red rice was dried and mixed well with untreated rice. Soybean powder (10 g) and broth (50 ml) were added per 100 g of the mixture and the composition was sterilized. The mixture is cooled to 30-40 ° C. and 10-20 ml of liquid Monascus strain (CGMCC No. 0272)
And fermented at 30 to 34 ° C. for 3 to 4 days and at 23 to 25 ° C. for 15 days or more. The mixture was sterilized at 100-121 ° C and dried under vacuum. The red rice product was crushed into tablets.

(C) Other mediums are 4% malt juice, 6% malt sugar
Prepared with 1% yeast extract powder, 6% peptone and water (pH = 3). Soybean powder (15 g) and culture broth (50 ml) were added for every 100 g of milled round, non-sticky rice. The mixture is pasteurized at 121 ° C
Louver AS3.549 (20 ml) was inoculated. The fermentation was carried out at 25 ° C for 9 days or longer. After sterilization, the mixture was dried at 80 ° C.

Red rice was further processed into a concentrate by two alcohol (75%) extractions.
After distillation under vacuum, a concentrate was obtained and the alcohol was recovered. The resulting concentrate contained about 25 mg robastatin per gram red rice and was used as a raw material for the production of capsules or tablets.

(D) Another culture was prepared containing 4% malt juice, about 8% sugar, 2% yeast extract powder, 5% concentrated beef juice and water (pH = 3). It was
Culture medium (50 ml) was added for every 100 g of rice and the mixture was sterilized at 121 ° C. After cooling to below 40 ° C., the mixture was monascus arvidas (CGMCC No.
0317) and fermented at 25 ° C for 12 days or longer. The mixture is sterilized,
Dried This red rice formulation was ground to 200 mesh and granulated with alcohol for pill preparation.

(E) The broth is also 3% potato juice, about 6% sugar, 1.5%
Yeast extract powder, 4% peptone and water (pH = 3). Soybean powder (10 g) and culture broth (80 ml) were added per 100 g of rice and the mixture was sterilized by steam at 121 ° C. After cooling to below 40 ° C., the mixture was inoculated with Monascus pirosus satou (AS3.4444) at 30-34 ° C. for 3-4 times.
The cells were cultivated for a day, further cultivated at 100 to 121 ° C. for 10 days or more, and dried.

This red rice formulation was further processed into a concentrate by alcohol (75%) extraction. A small amount of insoluble starch was added for pill manufacture.

(F) Broth was also prepared with 3% potato juice, 5% sugar, 6% concentrated beef juice and water (pH = 3). 10-20% peanut flour was added to the culture broth (80 ml) for every 100 g of rice and the mixture was sterilized by steam at 121 ° C. After cooling to below 40 ° C, the mixture is monascus louver
Inoculated with van tigem (CGMCC No. 0315), 30-34 ° C
Cultured for 3 days. The temperature was lowered to 24 ° C. and the culture was continued for 15 days or longer. The mixture was steam sterilized at 121 ° C. and dried.

(G) The medium was also 3% corn juice or 3% potato juice, 6% sugar, 1.5% yeast extract powder, 4.5% peptone and water (p.
H = 3). 5-20% soybean powder and 80 ml of culture broth
It was added every 100 g of millet. The mixture is sterilized by steam at 121 ° C,
It was cooled to a temperature of 40 ° C. or lower, inoculated with Monascus pirosus (AS3.4633), and cultured at 25 ° C. for 8 days or more. The mixture was sterilized at 121 ° C and dried under vacuum at a temperature of 60-80 ° C.

(H) Medium was prepared containing 4% potato juice, 7% sugar, 8% peptone and water (pH = 3). The culture solution (60 ml) was added to every 100 g of rice, and the mixture was sterilized at 121 ° C. After cooling to a temperature below 40 ° C., the mixture is inoculated with Monascus pavigerus satoto (AS3.4445) at 30-34 ° C.
Cultured for 3 days. The temperature was lowered to 25 ° C. and the culture was continued for 9 days or longer.
The mixture was sterilized at 121 ° C and dried at 80 ° C.

(I) Vehicle is 5% soy milk, 5% glucose, 2% yeast extract powder,
It was prepared with 5% soy peptone and water (pH = 3). Culture solution (80 ml
) Was added per 100 g of rice and the mixture was sterilized by steam at 121 ° C. 40
After cooling to a temperature below ℃, the mixture was mixed with Monascus Pirosus Sato (AS3.4
646) and cultured at 30 to 34 ° C. for 3 days. The temperature was lowered to 23 to 25 ° C, and the cells were cultured for 9 days or longer. The mixture is sterilized by steam at 121 ° C, 8
Dried at 0 ° C.

(J) Vehicle was prepared containing 4% potato juice, 4% sugar, 3% yeast extract powder and water (pH = 3). Silkworm pupa powder (5 g) and culture broth (60 ml) were added per 100 g of rice and the mixture was sterilized by steam at 121 ° C. After cooling to a temperature below 40 ° C., the mixture was inoculated with Monascus firidinosus satto (AS3.569) and incubated at 30-34 ° C. for 3 days. The temperature was lowered to 23 to 25 ° C, and the culture was continued for 9 days or longer. The mixture is 121 ℃
Sterilized by steam at 60 ° C. and dried under vacuum at 60-80 ° C.

(K) Vehicle was prepared containing 3% malt juice, 5% sugar, 6% concentrated beef juice and water (pH = 3). The culture medium (80 ml) was added to every 100 g of rice, and the mixture was sterilized by steam at 121 ° C. After cooling to a temperature of 40 ° C. or lower, the mixture was inoculated with Monascus firidinosus satto (AS3.1098) and incubated at 30 to 34 ° C. for 3 days. The temperature was lowered to 23 to 25 ° C, and the culture was continued for 9 days or longer. The mixture was sterilized by steam at 121 ° C and dried at a temperature of 80 ° C.

[0076]   (L) The following procedure was used for large scale fermentation.

(1) [Dip of Rice] Rice (500 kg) was placed in several layers of baskets. Rice husks are washed with water and rice is soaked in water for 16-24 hours. The rice was dredged from water and dried (water content is about 22-24%).

(2) [Steam treatment of rice] The dried rice is poured into a rice steamer to obtain 50-70.
Steamed for minutes. The steamed rice was spread on bamboo floors or in baskets, dispersed and cooled to temperatures below 40 ° C. Rice was inoculated with about 20 kg of a solid Monascus strain and 2.5-3 kg of acetic acid and stirred.

(3) [Fermentation] Rice was cut back several times a day for the first 3 days. Temperature is 30
Controlled between 0 ° C and 34 ° C. After 3 days, the temperature was reduced to 23-25 ° C. The rice was cut once or more daily, during which time water (pH value was adjusted to 3.5 with acetic acid) was added in an amount depending on the humidity of the fermenting mixture. The mixture was fermented for more than 15 days.

[0080]   (4) [Storage] After the fermentation process, the mixture was sterilized, dried and stored.

The large-scale fermentation process is used for all the above-mentioned media and preparation processes by adding the individual characteristics of the other ingredients. It should be noted that forced ventilation can be used for the fermentation process, but the returning air must be sterilized.

Example 2-Pharmacology and Toxicology The pharmacological and toxicological studies of red rice of the present invention were conducted in experimental animal models.
Red rice dramatically reduces total cholesterol (TC) in the blood of endogenous hyperlipidemic rabbits and TC and total triglycerides (TG) in exogenous hyperlipidemic rabbits
It was shown to suppress the formation of speckles of arteriosclerosis and the adhesion of fat to the liver in hyperlipidemic rabbits, and reduce TC and TG in the blood of quail with hyperlipidemia. It was

[0083] In the acute toxicity study, it is impossible to LD ₅₀ value is determined. The highest antitoxic dose of red rice in mice is above 16 g / kg, which is more than 533 times the dose used in clinical therapy. In addition, in another experiment, rats were 4
He was continuously forcibly fed red rice for a month, did not die, and showed no toxic effects from this drug. Hematological indicators, main visceral indicators, blood biological indicators,
Daily urinalysis and pathological examination showed no difference between experimental and control groups.

Example 3-Human Clinical Study I The following two examples include methodology and the results of two human clinical trials conducted in China. Trials determine the efficacy of red rice products in regulating circulating blood fat and lipoprotein levels in humans, elucidating symptoms according to traditional Chinese medicine, and establishing red rice product safety Planned that.

In a first randomized human clinical trial, 446 patients with hyperlipidemia were divided into two treatment groups. The patient was also diagnosed as suffering from spleen dysfunction and disease by traditional Chinese medicine.

Group 1 (324 patients) received capsules of Ciuscan containing 0.3 g of red rice product. The second group (122 patients) is a control, a traditional Chinese herbal medicine, a fat-regulating agent (gynostemma Pen).
I received a Jiaogulan tablet containing taphyllum).

All patients with primary hyperlipidemia stopped using fat regulators in their blood for 2 to 4 weeks and received dietary advice prior to the start of the trial. Blood samples were taken and laboratory tests were performed to determine eligibility for the study. Next criteria
Only patients who met the criteria were included in the trial. Total cholesterol in blood (TC
)> 230 mg / dl (5.95 mmol / L) and total triglycerides (TG)
> 200 mg / dl (> 2.26 mmol / L / L). Also, men <40 mg /
dl (1.04 mmol / L), female <45 mg / dl (1.16 mmol / L)
High viscosity lipoprotein cholesterol (HDL-C) of)) was considered as a reference. All patients were diagnosed by traditional Chinese medicine as having defective spleen function and excessive sputum. The patient also had the following symptoms: Weakness in the limbs, weak breathing, chest tightness and pain, loss of appetite, swelling of the area of the stomach, white spots on the tongue, thick white or thick slimy white lichen, tense or hesitant and weak to hold pulse.

Patients with the following diseases or disorders were excluded from the trial. Myocardial infarction, cerebrovascular disease,
Significant trauma or major surgery, renal disease syndrome, hypothyroidism, distressed or chronic hepatobiliary disease, diabetes, gout, general allergic reaction and psychosis for the past 6 months.

The total number of patients enrolled was 446. There were 188 male and 126 female patients in the group treated with red rice. The male to female ratio was 1.38: 1 with a mean age of 56.0 ± 9 years. There were 73 male patients and 45 female patients in the control group. The ratio of men to women is
At 1.49: 1, the average age was 56.4 ± 9.1 years. There were no differences between the two groups seen in baseline parameters including disease course such as age, sex, blood fat and lipoprotein levels (P> 0.05).

The group treated with red rice received two capsules of Ciuscan orally twice daily for 8 weeks. The control group took 3 tablets of Jaogran twice daily for 8 weeks. All patients maintained the same lifestyle and similar habits as before.

The following tests were performed 4 times in 8 weeks. Measurements of body weight, blood pressure and heart beat were performed. In addition, electrocardiogram and daily physical exercise were performed. The next parameter is
It was monitored by laboratory tests. Blood urea nitrogen (BLTN), creatinine, blood glutamate pyruvate aminotransferase (SGPT), blood glucose and creatine kinase (CK).

To determine the levels of fat and lipoproteins in the blood, fasted (12 hour) venous blood samples were taken not only on alcoholic drinks on the last meal before the test, but also on foods with high fat content. It was taken from a patient who did not take it. Blood obtained from patients was immediately separated and stored at -20 ° C for analysis. TC, TG and HD
LC was analyzed and the LDL-C value was calculated by the following formula. LDL-C = TC
-HDL-C- (TG / 2.2) The efficacy of treatment was published by the Ministry of Health of Chaina, "China Trial Management, for the treatment of hyperlipidemia with new Chinese substance drugs. It was evaluated according to the following criteria set out in "Treatment".

1. Healing: All symptoms removed or 90% of all symptom scores
Reduction of the above and return of all laboratory laboratory parameters to normal.

2. Effective: Symptoms were significantly alleviated. That is, the symptom score of 70 to 89
% Reduction. Blood fat and lipoproteins do not reach normal, but are improved in one of the following ways: 1) Reduction of TC ≧ 20%, 2) Reduction of TG ≧ 40%, 3) (TC
-HDL-C) / HDL-C reduction ≧ 20%, 4) HDL-C increase> 10 mg
/ Dl.

3. Improvement: The symptoms were alleviated. That is, the symptom score was reduced by 30 to 69%. Blood fat and lipoproteins were not normal, but improved in one of the following ways: 1) 10-20% reduction of TC, 2) reduction of TG ≧ 20%, but <40%, 3
) (TC-HDL-C) / HDL-C reduction ≧ 10%, but <20%, 4) HDL
-C increase> 4 mg / dl (0.14 mmol / L, but <10 mg / dl.

4. No efficacy: Symptom scores are reduced by less than 30% and laboratory test parameters are below the criteria for efficacy.

All data were used for statistical analysis (student t test, chi-square test, Ridit analysis for hierarchical data, and U diagram for percentile analysis as appropriate). Be assigned).

[0098]

[Table 2]

[0099]

[Table 3]

Table 1 shows a comparison of overall efficacy. The score of the group that received red rice (treatment group) was significantly higher than that of the control group (X ² = 9.7, P <0.00).
1).

The percentage of patients in the treatment group with reported elimination of symptoms diagnosed by traditional Chinese medicine was significantly higher than that in the control group (P <0.05-0).
． 001). These symptoms include: tongue condition (white spots on tongue, thick, slimy white lichen), veins (tight, hard-to-grab or weak hesitant pulse), chest tightness,
Loss of appetite and swelling of the abdomen.

With respect to the levels of fat and lipoproteins in blood, the efficacy of healing or reduction of total cholesterol and triglycerides in blood of the treatment group was higher than that of the control group. The score and level of normalization and increase of HDL-C in the treatment group and the score of the index of atherosclerosis were also better than those of the control group (P <0.001).

Table 2 shows that both the Chizucan-treated group and the control group had significant levels of TC, TG, (TC-HDL-C) / HDL-C, HDL-C, which were markedly higher in blood levels. Indicates that the desired change has been demonstrated. It was found that the effect of Ciuscan was superior to that of Jaogran.

It was observed that the higher the standards of TC and TG in blood, the more effective the reduction of TC and TG after the use of chizucan. Greater increases were also observed for HDL-C after treatment of patients with lower starting criteria.

[0105]

[Table 4]

[0106]

[Table 5]

Considering the effect of chiuzucan on apolipoprotein as a-I and apolipoprotein B, the levels of apoA-I in blood in both groups were elevated after treatment. Statistical results show significant changes in the levels of Apo AI after 4 weeks. However, the level of Apo B was not statistically significantly reduced, with some reduction in both groups. The treatment group showed better improvement of apolipoprotein B and apo AI / Apo B over the control group.

Regarding rheology, there were significant changes in blood sedimentation and K values in both post-treatment groups (P <0.05-0.001). However, the treatment group showed better results than the control group (P <0.05-0.001).

All 446 patients underwent the following laboratory tests before and after treatment. Blood urea nitrogen (BUN), creatine, blood glutamate pyruvate aminotransferase (SGPT, ALT), blood glucose and creatine kinase (C
K), and daily blood and urine tests. No clinically meaningful changes were seen until the end of the trial.

Some patients began to feel a burning sensation in the stomach (6 patients, 1.
8%), experienced gastric filling (3 patients, 0.9%) and suffered from dizziness (1 patient, 0.3%). All patients had spontaneous relief of all symptoms without treatment before the end of the trial. Two patients suffered gastritis after taking Ciuscan and left the trial. The result is that Ciuscan reduces blood fat and triglycerides,
Suggest that it is a safe and effective drug.

In this trial, fat modifiers known in traditional Chinese medicine were used as active controls. The range of efficacy in the Chizucan treatment group was significantly higher than in the control group (P <0.001). In the chizucan-treated group, the high-viscosity lipoprotein cholesterol in blood was 19.6 as compared with the standard.
%, And total cholesterol, total triglycerides, low viscosity lipoprotein cholesterol and arteriosclerosis indices were reduced by 23%, 36.5%, 28.5% and 34.2%, respectively. It was also observed that the higher the levels of fat and lipoproteins in the blood, the more dramatic regulation of fat and lipoprotein levels can be achieved with Ciuscan treatment. In addition, Ciuscan can reduce apolipoprotein, blood sedimentation and blood sedimentation K value.

Overall, the results show that red rice is a safe and effective drug for regulating the levels of fat and lipoproteins in blood. In addition, red rice is TC of plasma
, Because it not only markedly decreased the index of TG and arteriosclerosis but also significantly increased plasma apolipoprotein at a-I level, it was suggested that coronary artery disease and cerebrovascular disease due to hyperlipidemia and athyrosis. It can be used as a therapeutic drug.

Example 4-Human Clinical Trials II In this clinical trial, 84 patients with hyperlipidemia and 56 patients diagnosed with atherosclerosis It was divided into two treatment groups: a group treated with capsules and a control group treated with Jaogran tablets.

All patients were diagnosed with hyperlipidemia according to the criteria set out in “China Trial Control, Treatment of Hyperlipidemia with New Chinese Substance Drugs” published by the Ministry of Health of China. Blood samples were collected from patients with abnormal fat and lipoproteins twice a week prior to the trial, after 2 to 4 weeks of dietary advice. Only patients who met the criteria, ie total cholesterol (TC) in blood> 230 mg / dl (5.95 mmol / L) and total triglycerides (TG)> 200 mg / dl (2.26 mmol / L) were allowed to participate in the trial. Was given. High viscosity lipoprotein cholesterol (HD
L-C) was considered as a reference. Male <40 mg / dl (1.04 mmol / L
), Women <45 mg / dl (1.16 mmol / L).

Symptoms include limb pressure, weak breathing, chest pain and pressure, loss of appetite, swelling of the stomach area, white spots on the tongue, thick white or slimy white lichen on the tongue, tight grip Includes weak or hesitant weak pulses.

The severity of symptoms recognized by traditional Chinese medicine is scored as follows.

Weak Breathing 0 None (-) No Weak Breathing 2 Mild (+) Weak Breathing During Physical Activity 3 Moderate (++) Moderate Weak Breathing During Physical Activity 4 Severe (+++) With Weak Breathing At Rest Hands And Feet Pressure 0 0 No (-) No limb pressure 2 Mild (+) Occasionally limb pressure 3 Moderate (++) Frequent moderate limb pressure 4 Severe (++) severe limb pressure Chest compression and Pain 0 None (-) Chest compression and no pain 2 Mild (+) Occasionally chest compression and pain 3 Moderate (++) Frequent chest compression and pain 4 Severe (++) Chest compression and pain at rest Yes Loss of appetite 0 No (-) With normal appetite 2 Mild (+) 1/4 to 1/3 loss of appetite 3 Moderate (++) 1/3 to 1/2 loss of appetite 4 Severe (+++) 1 / 2 or later Loss of appetite Upper abdominal distension 0 No (-) No this sign 2 Mild (+) Sometimes this sign 3 Moderate (++) Frequent this sign 4 Severe (+++) Severe abdominal distension 0 Tongue image 0 Normal (-) 1 Abnormality (+) Pulse status 0 Normal (-) 1 Abnormality (+) Severity of symptom Mild score ≤ 12 Moderate score 12 to 20 Severe score> 20 Patients with primary hyperlipidemia were enrolled.

[0118]   The criteria for excluding patients are as follows:

A. Myocardial infarction, cerebrovascular disease, major trauma or major surgery for the last 6 months b. Kidney disease syndrome, hypothyroidism, distressed or chronic hepatobiliary disorders, diabetes, gout, c. Hereditary hypercholesterolemia (monogenic hypercholesterolemia), d. Other medicines, namely phenothiazines, beta-adrenergic blockers,
Corticosteroids, oral contraceptives, e. Patients with other fat modifiers and heparin or thyroidzation in the last 4 weeks, f. Women who are pregnant and breastfeeding g. Patients with diseases of other organs, and h. Hylaxis syndrome and psychosis.

The total number of patients enrolled was 116. There were 84 patients in the treatment group and 32 patients in the control group. No categorical differences in age, sex and illness history were found between the two groups.

A randomized, single-blind trial was performed on two groups. The treatment group (84 cases) took two Ciuzcan capsules (ie, the red rice product of the present invention) twice a day. Control group (3
2 cases) 3 jao grand tablets (Chinese materia
Medica, Shanxi factory, lot number: 940730). One course of treatment lasted 8 weeks.

Measurements of blood fat and lipoproteins and other scoring were performed before treatment and 4 and 8 weeks after treatment. Safety tests were performed before and after treatment. Fasted venous blood samples were collected. Patients were not allowed to take alcohol or foods with high fat content on their last meal.

The following safety tests were performed. Blood and urea nitrogen (BUN), creatine, glutamate pyruvate aminotransferase (SGPT, ALT) in blood, glucose and creatine kinase (CK) in blood. Total cholesterol in blood (T
C), levels of total triglyceride (TG) and high viscosity lipoprotein cholesterol in blood were measured to determine efficacy. Other relevant clinical signs were recorded, such as hypertension, heart beating and palpation of the liver and spleen.

The efficacy of the treatment was evaluated according to the following criteria set out in “China Trial Control, Treatment of Hyperlipidemia with New Chinese Substance Drugs” published by Ministry of Health of China.

1. Cure: All symptoms eliminated or a 90% or greater reduction in all symptom scores and all laboratory laboratory parameters reached normal levels.

2. Effective: Symptoms were significantly alleviated. That is, the symptom score of 70 to 89
% Reduction. Blood fat and lipoproteins did not reach normal levels, but improved in one of the following ways: 1) Reduction of TC ≧ 20%, 2) Reduction of TG ≧ 40%, 3
) (TC-HDL-C) / reduction of HDL-C ≧ 20%, 4) increase of HDL-C>
10 mg / dl.

3. Improvement: The symptoms were alleviated. That is, the symptom score was reduced by 30 to 69%. Blood fat and lipoproteins did not reach normal levels, but improved in one of the following ways: 1) 10-20% reduction of TC, 2) reduction of TG ≧ 20%, <40%, 3) reduction of (TC-HDL-C) / HDL-C ≧ 10%, <20%
4) Increase in HDL-C> 4 mg / dl (0.14 mmol / L) 4. No efficacy: Symptom scores are reduced by less than 30% and laboratory parameters are below the criteria for efficacy.

All data are subject to statistical analysis. Student's t test, chi-square test for counting data, and redit analysis were used when appropriate.

[0129]   Table 5 shows a comparison of the overall efficacy scores of the two groups.

[0130]

[Table 6]

The total efficacy score of the treatment group was significantly higher than that of the control group (X ² −
22.95, P <0.01).

[0132]   Table 6 shows a comparison of efficacy as defined by traditional Chinese medicine standards.

[0133]

[Table 7]

The percentage of patients in the treatment group with reported elimination of symptoms diagnosed by traditional Chinese medicine was similar to white spots on the tongue, especially in chest pain and pressure, loss of appetite, area of stomach. In terms of expansion, it was considerably higher than that of the control group (P
<0.05).

[0135]   The changes in the level of total cholesterol in the blood are shown in Table 7.

[0136]

[Table 8]

The score of healing or reduction of the level of total cholesterol in blood in the treatment group was higher than that of the control group.

[0138]   The changes in the levels of total triglycerides in the blood are shown in Table 8.

[0139]

[Table 9]

No significant difference in healing or reduction in the level of total cholesterol in the blood was observed between the two groups.

Changes in high lipoprotein-cholesterol levels are shown in Table 9.

[0142]

[Table 10]

[0143]   Similar efficacy was seen in two groups for normalizing or increasing HDL-C.

Table 10 shows the change in the index of arteriosclerosis, which is the ratio of (TC-HDL-C) / HDL-C.

[0145]

[Table 11]

The data in Table 10 shows that both the Chizucan treated group and the control group
It shows that the level of HDL-C in blood was significantly improved. It was found that the effect of chizucan was superior to that of control.

Table 11 shows the effect of Ciuscan on regulating the levels of fat and lipoproteins in blood (X +/- S).

[0148]

[Table 12]

[0149] Table 11 shows that Ciuzcan was found to contain TC, TG, (TC-HDL-C) / HD in blood.
It shows that the control group only significantly improves TG, while significantly improving the level of LC. Ciuscan treatment was found to regulate TC, LDL-C more effectively than controls.

Table 12 shows the efficacy of Ciuscan treatment based on different criteria of fat and lipoprotein in blood.

[0151]

[Table 13]

The higher the standards of TC and TG in the blood, the greater the reduction achieved after the use of chizucan.

The results showed that the healing score and efficacy score were 46.4% (38/84) and 29.8% (25/84) in the Ciuscan-treated (red rice treatment) group, respectively, and the control It shows that it was 9.4% (3/32) and 18.8% (6/32) in the group. The overall efficacy ratio (72%) in the treatment group was significantly higher than that in the control group (28.2%, P <0.001). Between the two groups,
There were significant differences regarding the improvement of TC, LDL-C and (TC-HDL-C) / HDL-C. There were no significant clinically meaningful changes in the following parameters during and after treatment. Examination of blood glutamate pyruvate aminotransferase (SGPT), blood and urea nitrogen (BUN), creatine, blood glucose and daily urine and blood. In these cases, an increase in creatine kinase (CK) in the treated group (2522 vs. 200 IU / L for the normal standard)
60466 IU / L) and increase of creatine kinase in control group (
256 IU / L) was reported. No clinical signs were observed in these cases. The results show that the red rice product of the present invention is safe and acceptable as a fat regulator.

Other Embodiments Although the present invention has been described in connection with its detailed description, the foregoing description is intended to be exemplary and is defined by the scope of the appended claims. It should be understood that it is not intended to limit the scope of the invention. Other aspects, advantages, and modifications are within the scope of the claims.

[Procedure for Amendment] Submission for translation of Article 34 Amendment of Patent Cooperation Treaty

[Submission date] February 24, 2000 (2000.2.24)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Contents of correction]

[Claims]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/365 A61K 31/365 4C087 35/74 35/74 Z 4C088 35/78 35/78 U 4C206 A61P 1 / 16 A61P 1/16 3/06 3/06 7/02 7/02 9/00 9/00 9/10 9/10 9/12 9/12 C12N 1/14 C12N 1/14 A (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ , BY, KG, KZ, MD, RU, TJ , TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE , GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, L U, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Chang Mao Liang Peking 100080, 30 Haidian Nan, Pekin Aerospace Great Wall Building, Room 619-623 (72) Inventor Peng Shuu People's Republic of China Peking 100080, 30 Haidian Nan Le, Kin Aerospace Great Wall Building, Room 619-623 (72) Inventor Chow Yufan, People's Republic of China Pekin 100080, 30 Haidian Nanru, Pekin Aerospace Great Wall Building, Room 619-623 F-Term (Reference) 4B018 MD08 MD10 MD49 MD80 ME04 MF01 MF13 4B023 LC09 LE30 LG01 LP16 4B064 AD65 AE46 CA05 DA06 4B065 AA58X AC14 BB26 CA10 CA18 CA41 4C086 AA01 AA02 AA04 BA07 GA17 MA01 MA02 MA04 MA05 NA14 ZA36 ZA40 ZA42 ZA43 ZA45 ZC33 4C087 AA01 AA02 AA03 AA04 BC10 CA37 ZA36 ZA40 ZA42 ZA43 ZA45 ZC33 4C088 AB74 AC04 BA32 CA25 MA02 ZA36 ZA40 ZA42 ZA43 ZA45 ZC33 4C206 AA01 AA02 DB16 DB42 KA01 MA01 MA02 MA04 MA05 ZA36 ZA40 ZA42 ZA43 ZA45 ZC33

Claims (20)

[Claims] 1. A composition for treating elevated cholesterol and / or triglycerides in blood, which comprises a red rice product comprising at least about 0.05% by weight of Robustatin. 2. The red rice product is obtained by culturing a strain of Monascus that produces Robustatin in a culture medium comprising rice, and removing the culture medium to provide a solid residue. The composition of claim 1 which is a product of a process comprising sterilizing the solid residue to provide a. 3. The strain of Monascus is Monascus Albius Sato AS3.570,
AS 3.4440, CGMCC No. 0317, Monascus Pirosus Sato AS3.4444, AS3.4633, AS3.4646, AS3.4647
, Monascus Pavigers Sato AS3.4445, Monascus Louver
Fan Tiegem AS3.549, CGMCC No. 0315, CGMCC
No. 0316, Monascus Paxie Ringerzyme AS3.4453,
Monascus Firidinosus Sato AS3.569, AS3.1098, AS
3.2091, AS3.2093, AS3.2134, IFFI05035 and Monascus perpleus Went CGMCC No. The composition according to claim 2, wherein the composition comprises one strain selected from the group consisting of 0272. 4. The composition of claim 2, wherein said step further comprises extracting said solid residue with ethanol. 5. A Ronasstatin-producing Monascus strain is provided which provides a solidified red yeast rice in a culture medium comprising rice at a temperature of about 15 ° C. to about 35 ° C. for about 2 days to about 20 days. A method of producing improved red rice comprising culturing the strain of Monascus for a day and drying the solidified red rice to provide improved red rice. 6. The strain of Monascus is Monascus Albius Sato AS3.570,
AS 3.4440, CGMCC No. 0317, Monascus Pirosus Sato AS3.4444, AS3.4633, AS3.4646, AS3.4647
, Monascus Pavigers Sato AS3.4445, Monascus Louver
Fan Tiegem AS3.549, CGMCC No. 0315, CGMCC
No. 0316, Monascus Paxie Ringerzyme AS3.4453,
Monascus Firidinosus Sato AS3.569, AS3.1098, AS
3.2091, AS3.2093, AS3.2134, IFFI05035 and Monascus perpleus Went CGMCC No. The method according to claim 5, wherein the strain comprises one strain selected from the group consisting of 0272. 7. The culture medium further comprises from about 2% to about 6% sugar and from about 2% to about 7% additional carbon source selected from the group consisting of glycerin, malt and potato juice. 6. The method of claim 5, comprising about 0% to about 3% peptone, about 0% to about 3% concentrated beef juice, and about 2% to about 4% defoamer. 8. The strain of claim 5, wherein the strain is cultured at about 30 ° C. to about 34 ° C. for about 2 days to about 4 days, and at about 20 ° C. to about 25 ° C. for at least about 4 days. the method of. 9. The method of claim 5, further comprising extracting the red rice modified to provide an ethanol extract with an ethanol solution and drying the extract. 10. The method of claim 9, wherein the ethanol solution comprises about 75% to about 95% aqueous ethanol. 11. A strain of Monascus, which is capable of producing about 0.5% of Robustatin in the culture. 12. Monascus Albius Sato AS3.570, AS3.4440, CGM
CC No. 0317, Monascus Pirosus Sato AS3.4444, AS
3.4633, AS3.4646, AS3.4647, Monascus Pavigers Sato AS3.4445, Monascus Louver van TiegemAS3
． 549, CGMCC No. 0315, CGMCC No. 0316, Monascus Paxie Ringerzyme AS3.4453, Monascus Firidinosus Sato AS3.569, AS3.1098, AS3.2091, AS3.2.
093, AS3.2134, IFFI05035 and Monascus Perpleus Went CGMCC No. 12. The Monascus perpleus pent according to claim 11, which is a strain selected from the group consisting of 0272. 13. A method of treating or preventing cardiovascular disease in a mammal comprising administering to the mammal a red rice fermentation product comprising an effective amount of 0.5% Robustatin. 14. The method of claim 13, wherein the red rice fermentation product is produced from the product of fermentation of a strain of Monascus that produces at least one robastatin. 15. The cardiovascular disease is selected from the group consisting of myocardial infarction, coronary heart disease, hypertension, hypotension, atherosclerosis and arteriosclerosis. The method described. 16. A method of treating or preventing stroke, cerebral thrombosis, which comprises administering an effective amount of a red rice fermentation product. 17. A method of treating or preventing a fatty liver condition in a human comprising administering to the human an effective amount of a red rice fermentation product. 18. A method of reducing blood cholesterol and triglyceride levels to normal levels in a human in need thereof, which comprises administering an effective amount of a red rice fermentation product. 19. A pharmaceutical or therapeutic for treating elevated cholesterol and / or triglycerides in the blood, characterized in that it comprises an effective amount of red rice product and a pharmacologically acceptable additive. Nutritional prescription. 20. The formulation as claimed in claim 19, wherein the formulation comprises about 10 mg of Robustatin.
Prescription described.